The objective of the proposed research is to secure definitive information at the molecular level about the mechanism by which ferritin sequesters and subsequently mobilizes metabolic iron. The experimental approach in this proposal is based on the unique structural features of apoferritin. It is proposed to study the selectivity of apoferritin with respect to what can pass into the interior of this hollow shell. The physical-chemical approach to be employed is to measure the rates of passive diffusion into apoferritin of a number of compounds of increasing Stokes radii and differing charge properties. Results from these measurements will yield information about the size and charge discriminatory properties of the apoferritin channels with respect to the passive diffusion of small molecules (such as potential iron chelates) in and out. Based on information from the aforementioned experiments, the kinetics of iron accumulation with various mononuclear chelates of Fe plus2 and Fe plus3 will be examined with respect to the "active" shuttling of iron into and out of the protein shell. Finally, chemical modification of selected amino acid side chains will be employed to determine the types of amino acid residues which participate in the passage of iron (or its chelates) through the channels. The results of these findings should not only better explain the role of ferritin in such widely divergent maladies of iron metabolism as anemia and hemochromatosis, but it may offer new options for their clinical treatment.